Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

• HIV Human Immunodeficiency Virus
• RT reverse transcriptase
• the first RT inhibitors were nucleoside analogs such as AZT and ddl. Although such nucleoside RT inhibitors were frequently effective against the wild 7 type virus, any single-drug treatment has been hobbled by the virus's ability to readily produce drug-resistant mutants.
• NNRTIs non-nucleoside RT inhibitors
• DAPY diarylpyrmidines
• Diaryl compounds similar to Etravirine and Rilpivirine where the pyrimidine moiety is replaced by a purine are described in WO 2005/028479, which also is assigned to Janssen.
• dashed line represents a double bond that may be located either between A and C(V) or between C(V) and D;
• A is S or C(Z);
• D is S or C(W); provided that one and only one of A and D is S;
• T is NH, O, or S
• W and Z are, independently, H, F, Cl, Br, Ci-C 6 alky!; C 2 -C 6 alkenyl; OC 1 -C 6 alkyl; C 3 -C 6 cycloalkyl; OC 3 -C 6 cycloalkyl, phenyl, or benzyl, wherein alkyl, alkenyl, cycloalkyl, and phenyl groups and the phenyl moiety of the benzyl group are optionally substituted with 1-3 groups selected from halogen, CF 3 , C 1 -C 3 alkyl, and OCi-C 3 alkyl
• V is H, halogen, C 1 -C 6 alkyl; or V and W, together with the ring atoms to which they are attached, form an additional, fused 5-, 6-, or 7- membered ring, optionally containing one or two heteroatoms, which additional ring may be saturated, unsaturated, or aromatic; or V and Z, together with the ring atoms to which they are attached, form an additional, fused 5-, 6-, or 7- membered ring, optionally containing one or two heteroatoms, which additional ring may be saturated, unsaturated, or aromatic;
• Ar is selected from (a), (b), (c), and (d) below:
• R 4 , R 5 and each R 6 are independently selected from H, F, Cl, Br, CH 3 , CF 3, CH 2 F, CHF 2 , isopropyl, cyclopropyl, OCH 3 , OH, OCF 3 , NH 2 , and NHCH 3 , or R 6 and R p on adjacent ring atoms, together with the ring atoms to which they are attached, form an additional fused five-membered ring;
• Q and Q 1 are independently selected from N and CH;
• R 7 is Cl, Br, I, CH 3 , CF 3 , OCH 3 , isopropyl, cyclopropyl, /-butyl, or cyclobutyl; and R 8 - R" are, independently, H or CH 3 .; or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, ester., tautomer or prodrug thereof.
• the invention provides or contemplates a compound of formula IA where Ar is selected from 2-chloro-4-cyclopropyl phenyl; 2-methyl-4-cyclopropyl-naphth-l-yl; 2,6-dimethyl-4- cyanophenyl; 2,6-dimethoxy-4-cyanophenyl; 2,6-dimethyl-4-(2-cyanoethenyl) phenyl; 2,6-dimethoxy-4-(2- cyanoethenyl) phenyl; 2-methyl-4-cyclopropyl phenyl; 2,6-dimethyl-4-cyclopropyl phenyl; 2,6-di- trifluoromethyl-4-cyclopropyl phenyl; 2,4,6-trimethyl phenyl; and 2,6-dimethyl-4-acetyl phenyl.
• Ar is selected from 2-chloro-4-cyclopropyl phenyl; 2-methyl-4-cyclopropyl-naph
• the invention contemplates a compound of formula IA where Ar is selected from the following: 5-cyclopropyl-8-quinolyl; 5-isopropyl-8-quinolyl; 5-cyano-8-quinolyl; 5- cyclopropyl-7-trifluoromethyl-8-quinolyl; 5-acetyl-8-quinolyl; 5-cyano-7-methoxy-8-quinolyl; 5-cyano-7- methyl-8-quinolyl; 5-cyclopropyl-7-trifluoromethoxy-8-isoquinolyl; 5-cyano-8-isoquinolyl; 5-cyano-7-methoxy- 8-isoquinolyl; 5-cyano-7-methyl-8-isoquinolyl; 5-cyclobutyl-7-difluoromethyl-8-isoquinolyl; 5,7-dimethyl-8- cinnolyl; 5-cyclopropyl-7-methyl-8-cinnolyl; and 5-(2-cyanoethenyl)
• the invention provides a compound of formula 1A-2
• this invention provides a compound of formula IA -4
• this invention provides a compound of formula IB
• the invention provides a compound of formula IB where Ar is (c). f001 S] In a more specific subgeneric embodiment, the invention provides a compound of formula IB where Ar is
• this invention provides a compound of formula IB-I .
• this invention provides a compound of formula IB-2.
• the invention provides compounds of any of IA-I, IA-2, IA-3, IA-4, IB-
• the invention provides compounds of any of IA-I , IA-2, IA-3,
• the invention provides compounds of any of IA-I , IA-2, IA-3,
• the invention provides compounds of any of IA-I , IA-2, IA-3,
• this invention provides or contemplates a compound of formula IA-I, IA-2, IA-3, or IA-4, where Ar is 2,6-disubstituted-4-cyclopropyl, 2,6-disubstituted-4-acetyl,
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where Ar is 4-cyano-2,6-di-methoxy phenyl or 4-cyano-2,6-di-mcthyl phenyl.
• this invention provides or contemplates compounds of formula IA-I , IA-2, IA-3, or IA-4, where V is H, halo, or methyl.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where A is S and W is H, phenyl, or benzyl.
• this invention provides or contemplates a compound of formula IA-I , IA-2, IA-3, or IA-4, where A is S and W is H, C 3 -C 6 cycloalkyl, or OC 3 -C 6 cycioalkyl.
• 00271 In another still more specific subgeneric embodiment, this invention provides or contemplates compounds of formula IA- 1, 1A-2, 1A-3, or IA-4, where A is S and W is H, unsubstituted C r C 4 alkyl, monosubstituted C r C 4 alkyl, or C 2 -C 3 alkenyl.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where A is S and W is H, halo, halomethyl, or methyl.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where A is S and V and W, together with the ring atoms to which they are attached, form an additional, fused 5-, 6-, or 7- membered carbocyclic ring.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where A is S and V and W, together with the ring atoms to which they are attached, form an additional, fused 5-, 6-, or 7- membered ring, which ring contains one or two heteroatoms selected from O, N, and S.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where D is S and Z is H, Ci-Ce alkyl, or C 2 -C 6 alkenyl.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where D is S and Z is H, C 3 -C 6 cycloalkyl, or OC 3 -C 6 cycloalkyl.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where D is S and Z is H, unsubstituted CpC 4 alkyl, monosubstituted Ci-C 4 alkyl, or C 2 -C 3 alkenyl.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where D is S and Z is H, halo, halomethyl, or methyl.
• this invention provides or contemplates a compound of formula IA-I, IA-2, IA-3, or IA-4, where D is S and Z is H, phenyl, or benzyl.
• this invention provides or contemplates compounds of formula IA-I , IA-2, IA-3, or IA-4, where D is S and V and Z, together with the ring atoms to which they are attached, form an additional, fused 5-, 6-, or 7- membered carbocyclic ring.
• this invention provides or contemplates compounds of formula IA- I, IA-2, IA-3, or IA-4, where D is S and V and Z, together with the ring atoms to which they are attached, form an additional, fused 5-, 6-, or 7- membered ring,, which ring contains one or two heteroatoms selected from O, N, and S.
• the invention provides for compounds of formula I and their pharmaceutically acceptable salts.
• the invention provides for compounds of formula I and their pharmaceutically acceptable solvates.
• the invention provides for compounds of formula I and iheir pharmaceutically acceptable hydrates.
• the invention provides for compounds of formula 1 and their pharmaceutically acceptable polymorphs. [0042
• the invention provides for compounds of formula l and their pharmaceutically acceptable tautomers.
• the invention provides for compounds of formula I and their pharmaceutically acceptable prodrugs.
• HIV-I human immunodeficiency virus type 1
• compositions comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
• the pharmaceutical compositions further comprise a pharmaceutically acceptable carrier.
• Such compositions may contain adjuvants, excipients, preservatives, agents for delaying absorption, fillers, binders, adsorbents, buffers, disintegrating agents, solubilizing agents, other carriers, and other inert ingredients. Methods of formulation of such compositions are well-known in the art.
• the pharmaceutical composition is in a form suitable for oral administration.
• the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulation, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
• the pharmaceutical composition is in unit dosage forms suitable for single administration of precise dosages.
• the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.S to about 50 mg/kg/day.
• the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.002 to about 6 g/day. In further or additional embodiments the amount of compound of formula I is about 0.005 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 5 g/day. In further or additional embodiments the amount of compound of formula 1 is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day.
• dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required.
• the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day. In some embodiments, the pharmaceutical composition is for administration to a mammal.
• the mammal is human.
• the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and/or adjuvant.
• the pharmaceutical composition further comprises at least one therapeutic agent
• the therapeutic agent is an HIV or AIDS drug, or a drug for the treatment of the symptoms of HlV or AIDS.
• the pharmaceutical composition is administered in combination with an additional therapy.
• the pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of formula 1.
• the method comprises contacting said reverse transcriptase enzyme with an amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, sufficient to inhibit said enzyme, wherein said enzyme is inhibited.
• the enzyme is at least about 1 % inhibited.
• the enzyme is at least about 2% inhibited.
• the enzyme is at least about 3% inhibited.
• the enzyme is at least about 4% inhibited.
• the enzyme is at least about 5% inhibited.
• the enzyme is at least about 10% inhibited. In further or additional embodiments the enzyme is at least about 20% inhibited. In further or additional embodiments the enzyme is at least about 25% inhibited. In further or additional embodiments the enzyme is at least about 30% inhibited. In further or additional embodiments the enzyme is at least about 40% inhibited. In further or additional embodiments the enzyme is at least about 50% inhibited. In further or additional embodiments the enzyme is at least about 60% inhibited. In further or additional embodiments the enzyme is at least about 70% inhibited. In further or additional embodiments the enzyme is at least about 75% inhibited. In further or additional embodiments the enzyme is at least about 80% inhibited. In further or additional embodiments the enzyme is at least about 90% inhibited.
• the enzyme is essentially completely inhibited.
• the reverse transcriptase enzyme is HlV reverse transcriptase.
• the reverse transcriptase enzyme is HlV-I reverse transcriptase.
• the HIV reverse transcriptase is resistant to non-nucleoside reverse transcriptase inhibitors.
• the contacting occurs within a cell.
• the cell is a mammalian cell.
• the mammalian cell is a human cell.
• the contacting occurs in vitro.
• the contacting occurs in vivo.
• the contacting occurs within the body of a subject infected with HIV.
• the reverse transcriptase enzyme is inhibited with a composition comprising a pharmaceutically acceptable salt of a compound of formula 1.
• Also described herein are methods of treating or preventing a disease in an individual comprising administering to said individual an effective amount of a compound of formula I or a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
• the disease is HIV.
• the disease is AIDS.
• the disease is ARC.
• the present invention provides pharmaceutical compositions, and prophylactic and therapeutic treatments, diagnostic and prognostic methods and kits, and pharmaceutical screening methods that take advantage of the anti-HIV activity of these compounds and compositions.
• Compounds that inhibit HIV replication are candidates for the prophylactic or therapeutic treatment of HlV infection.
• Prophylactic treatments are especially useful for persons at high risk of HIV infection.
• compositions comprising at least one compound of formula 1 and a second therapeutic agent or agents.
• the second therapeutic agent is used to prevent or treat HFV infection.
• the second therapeutic agent is used to treat an opportunistic infection associated with HTV infection.
• the second therapeutic is, for example, a protease inhibitor, a non- nucleoside reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, an antiretroviral nucleoside, an entry inhibitor, or any other anti-viral agent effective to inhibit or treat HlV infection.
• the second therapeutic agent is selected from the group consisting of zidovudine, didanosine, stavudine, interferon, lamivudine, adefovir, nevirapine, delaviridine, loviride, saquinavir, indinavir, and AZT.
• the second therapeutic agent is an antibiotic or acyclovir.
• the second agent is selected from immunomodulators, and entry inhibitors.
• compositions described herein can be administered orally, parentally (including subcutaneous injection, intravenous, intramuscular, intrasternal or infusion techniques), by inhalation spray, topically, by absorption through a mucous membrane, or rectally, in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants or vehicles.
• the compounds of the invention are potent against HIV and drug resistant strains of HIV.
• the present invention provides methods of inhibiting HIV infection in a CD4 + culture comprising contacting the cell at least one compound of formula I, either alone or in combination with a second therapeutic agent or a combination of other therapeutic agents.
• the therapeutic agent or agents are used to treat or prevent HIV infection.
• the present invention provides new compositions and methods for preventing or ameliorating viral, e.g., HIV infection, killing virally infected cells, e.g., HIV infected cells and generally, inhibiting viral, preferably HIV, replication.
• viral e.g., HIV infection
• the compounds described herein effectively inhibit HIV infection, kill HlV infected cells and/or prevent HIV infection in the individual.
• the compounds of the invention inhibit the replication of drug resistant strains of HIV.
• Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein.
• the foregoing techniques and procedures can be generally performed of conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification.
• groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.
• the compounds presented herein may possess one or more stereocenters and each center may exist in the R or S configuration, or combinations thereof. Likewise, the compounds presented herein may possess one or more double bonds and each may exist in the E (trans) or Z (cis) configuration, or combinations thereof. Presentation of one particular stereoisomer, regioisomer, diastereomer, enantiomer or epimer should be understood to include all possible stereoisomers, regioisomers, diastereomers, enantiomers or epimers and mixtures thereof. Thus, the compounds presented herein include all separate configurational stereoisomeric, regioisomeric, diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
• bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
• catalytic group refers to a chemical functional group that assists catalysis by acting to lower the activation barrier to reaction.
• an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc).
• substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum
• substitution or substitution patterns e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum
• any substituents described should generally be understood as having a maximum molecular weight of about 1 ,000 daltons, and more typically, up to about 500 daltons (except in those instances where macromolecular substituents are clearly intended, e.g., polypeptides, polysaccharides, polyethylene glycols, DNA, RNA and the like).
• C-C x includes C,-C 2 , Q-C 3 . . . C-C x .
• a group designated as "Ci-Q" indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, as well as the ranges Q-C 2 and Q-C 3 .
• Ci-C 4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, w ⁇ -butyl, sec-butyl, and /-butyl.
• a numerical range such as “ 1 to 10” refers to each integer in the given range; e.g., " 1 to 10 carbon atoms” means that the group may have I carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
• hydrocarbon as used herein, alone or in combination, refers to a compound or chemical group containing only carbon and hydrogen atoms.
• heteroatom or “hetero” as used herein, alone or in combination, refer to an atom other than carbon or hydrogen. Heteroatoms are may be independently selected from among oxygen, nitrogen, sulfur, phosphorous, silicon, selenium and tin but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others.
• alkyl refers to an optionally substituted straight- chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms.
• Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-metliyl-2 -propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 2-methyl-3- butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l -pentyl, 4-methyl-l-pentyl, 2-methyl-2- ⁇ entyl, 3- methyl-2-pentyl, 4-methyl-2 -pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l -butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hex
• a numerical range such as "C)-C 6 alkyl” or “Ci -6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated.
• alkylene refers to a diradical derived from the above-defined monoradical, alkyl. Examples include, but are nqt limited to methylene (-CH 2 -), ethylene (- CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), isopropylene (-CH(CH 3 )CH 2 -) and the like.
• alkenyl refers to an optionally substituted straight- chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
• a numerical range such as “C 2 -C 6 alkenyl” or “C 2 ⁇ alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl” where no numerical range is designated.
• alkynyl refers to an optionally substituted straight- chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms.
• Examples include, but are not limited to cthynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
• a numerical range such as "C 2 -C 6 alkynyl” or "C 2 . 6 alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl" where no numerical range is designated.
• alkynylene refers to a diradical derived from the above-defined monoradical, alkynyl. Examples include, but are not limited to ethynylene (-C ⁇ C-), propargylcne (-CH 2 -OC-) and the like.
• aliphatic refers to an optionally substituted, straight-chain or branched-chain, non-cyclic, saturated, partially unsaturated, or fully unsaturated nonaromatic hydrocarbon.
• the term collectively includes alkyl, alkenyl and alkynyl groups.
• heteroalkyl refers to optionally substituted alkyl, alkenyl and alkynyl structures respectively, as described above, in which one or more of the skeletal chain carbon atoms (and any associated hydrogen atoms, as appropriate) are each independently replaced with a heteroatom (i.e.
• haloalkyl refers to optionally substituted alkyl, alkenyl and alkynyl groups respectively, as defined above, in which one or more hydrogen atoms is replaced by fluorine, chlorine, bromine or iodine atoms, or combinations thereof.
• two or more hydrogen atoms may be replaced with halogen atoms that are the same as each another (e.g. difluoromethyl); in other embodiments two or more hydrogen atoms may be replaced with halogen atoms that are not all the same as each other (e.g.
• haloalkyl groups are fluoromethyl and bromoethyl.
• a non-limiting example of a haloalkenyl group is bromoethenyl.
• a non-limiting example of a haloalkynyl group is chloroethynyl.
• perhalo refers to groups in which all of the hydrogen atoms are replaced by fluorines, chlorines, bromines, iodines, or combinations thereof.
• perhaloalkyl refers to an alkyl group, as defined herein, in which all of the H atoms have been replaced by fluorines, chlorines, bromines or iodines, or combinations thereof.
• a non-limiting example of a perhaloalkyl group is bromo,chloro,fluoromethyl.
• a non-limiting example of a pcrhaloalkenyl group is trichloroethenyl.
• a non-limiting example of a perhaloalkynyl group is tribromopropynyl.
• carbon chain refers to any alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl group, which is linear, cyclic, or any combination thereof. If the chain is part of a linker and that linker comprises one or more rings as part of the core backbone, for purposes of calculating chain length, the "chain” only includes those carbon atoms that compose the bottom or top of a given ring and not both, and where the top and bottom of the ring(s) are not equivalent in length, the shorter distance shall be used in determining the chain length. If the chain contains heteroatoms as part of the backbone, those atoms are not calculated as part of the carbon chain length.
• cycle refers to any covalently closed structure, including alicyclic, heterocyclic, aromatic, heteroaromatic and polycyclic fused or non-fused ring systems as described herein. Rings can be optionally substituted. Rings can form part of a fused ring system.
• membered is meant to denote the number of skeletal atoms that constitute the ring.
• cyclohexane, pyridine, pyran and pyrimidine are six-membered rings and cyclopentane, pyrrole, tetrahydrofuran and thiophene are f ⁇ ve-membcred rings.
• fused refers to cyclic structures in which two or more rings share one or more bonds.
• cycloalkyl refers to an optionally substituted, saturated, hydrocarbon monoradical ring, containing from three to about fifteen ring carbon atoms or from three to about ten ring carbon atoms, though may include additional, non-ring carbon atoms as substituents (e.g. methylcyclopropyl). Whenever it appears herein, a numerical range such as “Cj-C 6 cycloalkyl " or "C 3 .
• cycloalkyl means that the cycloalkyl group may consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, i.e., is cyclopropyl, cyclobutyl, cyclopentyl or cyclohepty, although the present definition also covers the occurrence of the term " cycloalkyl " where no numerical range is designated.
• the term includes fused, non-fused, bridged and spiro radicals.
• a fused cycloalkyl may contain from two to four fused rings where the ring of attachment is a cycloalkyl ring, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
• Examples include, but are not limited to cyclopropyl, cyclopentyl, cyclohexyl, decalinyl, and bicyclo [2.2.1] heptyl and adamantyl ring systems.
• Illustrative examples include, but are not limited to the following moieties:
• cycloalkenyl refers to an optionally substituted hydrocarbon non-aromatic, monoradical ring, having one or more carbon-carbon double-bonds and from three to about twenty ring carbon atoms, three to about twelve ring carbon atoms, or from three to about ten ring carbon atoms.
• the term includes fused, non-fused, bridged and spiro radicals.
• a fused cycloalkenyl may contain from two to four fused rings where the ring of attachment is a cycloalkenyl ring, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
• Fused ring systems may be fused across a bond that is a carbon-carbon single bond or a carbon-carbon double bond.
• cycloalkenyls include, but are not limited to cyclohexenyl, cyclopentadienyl and bicyclo[2.2.1]hept-2-ene ring systems.
• Illustrative examples include, but are not limited to the following moieties: , and the like.
• alicyclyl or “alicyclic” as used herein, alone or in combination, refer to an optionally substituted, saturated, partially unsaturated, or fully unsaturated nonaromatic hydrocarbon ring systems containing from three to about twenty ring carbon atoms, three to about twelve ring carbon atoms, or from three to about ten ring carbon atoms. Thus, the terms collectively include cycloalkyl and cycloalkenyl groups.
• non-aromatic heterocyclyl and “heteroalicyclyl” as used herein, alone or in combination, refer to optionally substituted, saturated, partially unsaturated, or fully unsaturated nonaromatic ring monoradicals containing from three to about twenty ring atoms, where one or more of the ring atoms are an atom other than carbon, independently selected from among oxygen, nitrogen, sulfur, phosphorous, silicon, selenium and tin but are not limited to these atoms.
• the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others.
• a fused non-aromatic heterocyclic radical may contain from two to four fused rings where the attaching ring is a non-aromatic heterocycle, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
• Fused ring systems may be fused across a single bond or a double bond, as well as across bonds that are carbon-carbon, carbon-hetero atom or hetero atom-hetero atom.
• the terms also include radicals having from three to about twelve skeletal ring atoms, as well as those having from three to about ten skeletal ring atoms.
• Attachment of a non-aromatic heterocyclic subunit to its parent molecule can be via a heteroatom or a carbon atom.
• additional substitution can be via a hctcroatom or a carbon atom.
• an imidazolidine non-aromatic heterocycle may be attached to a parent molecule via either of its N atoms (imidazolidin-1-yl or imidazolidin-3-yl) or any of its carbon atoms (imidazolidin-2-yl, imidazolidin-4-yl or imidazolidin-5-yl).
• non-aromatic heterocycles contain one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups.
• Examples include, but are not limited to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6-tetrahydro ⁇ yridinyl, 2-pyrrolinyl, 3-pyrrolinyl, ind
• the terms also include all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
• aromatic refers to a planar, cyclic or polycyclic, ring moiety having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer.
• Aromatic rings can be formed by five, six, seven, eight, nine, or more than nine atoms.
• Aromatics can be optionally substituted and can be monocyclic or fused-ring polycyclic.
• aromatic encompasses both all carbon containing rings (e.g., phenyl) and those rings containing one or more heteroatoms (e.g., pyridine).
• aryl refers Io an optionally substituted aromatic hydrocarbon radical of six to about twenty ring carbon atoms, and includes fused and non-fused aryl rings.
• a fused aryl ring radical contains from two to four fused rings where the ring of attachment is an aryl ring, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
• aryl includes fused and non-fused rings containing from six to about twelve ring carbon atoms, as well as those containing from six to about ten ring carbon atoms.
• a non-limiting example of a single ring aryl group includes phenyl; a fused ring aryl group includes naphthyl, phenanthrenyl, anthracenyl, azulcnyl; and a non-fused bi-aryl group includes biphenyl.
• arylene refers to a diradical derived from the above- defined monoradical, aryl. Examples include, but are not limited to 1, 2-phenylene, 1 ,3-phenylene, 1 ,4- phenylene, 1 ,2-naphthylene and the like.
• heteroaryl refers to optionally substituted aromatic monoradicals containing from about five to about twenty skeletal ring atoms, where one or more of the ring atoms is a heteroatom independently selected from among oxygen, nitrogen, sulfur, phosphorous, silicon, selenium and tin but not limited to these atoms and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
• the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others.
• heteroaryl includes optionally substituted fused and non-fused heteroaryl radicals having at least one heteroatom.
• heteroaryl also includes fused and non-fused heteroaryls having from five to about twelve skeletal ring atoms, as well as those having from five to about ten skeletal ring atoms. Bonding to a heteroaryl group can be via a carbon atom or a heteroatom.
• an imidiazole group may be attached to a parent molecule via any of its carbon atoms (imidazol-2-yl, imidazol- 4-yl or imidazol-5-yl), or its nitrogen atoms (imidazol-1-yl or imidazol-3-yl).
• a heteroaryl group may be further substituted via any or all of its carbon atoms, and/or any or all of its heteroatoms.
• a fused heteroaryl radical may contain from two to four fused rings where the ring of attachment is a heteroaromatic ring and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
• a non-limiting example of a single ring heteroaryl group includes pyridyl; fused ring heteroaryl groups include benzimidazolyl, quinolinyl, acridinyl; and a non-fused bi-heteroaryl group includes bipyridinyl.
• heteroaryls include, without limitation, furanyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl, indolizinyl, isothiazolyl, isoindolyloxadiazolyl, indazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazinyl, pyrazolyl, purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazolyl,
• heteroarylene refers to a diradical derived from the above-defined monoradical heteroaryl. Examples include, but are not limited to pyridinyl and pyrimidinyl.
• heterocyclyl refers collectively to heteroalicyclyl and heteroaryl groups. Herein, whenever the number of carbon atoms in a heterocycle is indicated (e.g., Ci-C 6 heterocycle), at least one non-carbon atom (the heteroatom) must be present in the ring.
• Designations such as "Ci-Ce heterocycle” refer only to the number of carbon atoms in the ring and do not refer to the total number of atoms in the ring.
• Designations such as “4-6 membered heterocycle” refer to the total number of atoms that are contained in the ring (i.e., a four, five, or six membered ring, in which at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining two to four atoms are either carbon atoms or heteroatoms).
• heterocycles having two or more heteroatoms.. those two or more heteroatoms can be the same or different from one another.
• Heterocycles can be optionally substituted.
• Non-aromatic heterocyclic groups include groups having only three atoms in the ring, while aromatic heterocyclic groups must have at least five atoms in the ring. Bonding (i.e. attachment to a parent molecule or further substitution) to a heterocycle can be via a heteroatom or a carbon atom.
• Carbocycles can be optionally substituted.
• the term distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom which is different from carbon.
• halogen halo or halide as used herein, alone or in combination refer to fluoro, chloro, bromo and iodo.
• the lerm "oxo" as used herein, alone or in combination, refers to the diradical 0. [00102
• the term "carbonyl” as used herein, alone or in combination, refers to the diradical -C( O)-, which may also be written as -C(O)-.
• alkoxy refers to an alkyl ether radical, -O-alkyl, including the groups -O-aliphatic and -O-carbocyclyl, wherein the alkyl, aliphatic and carbocyclyl groups may be optionally substituted, and wherein the terms alkyl, aliphatic and carbocyclyl are as defined herein.
• alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
• reactant refers to a nucleophile or electrophile used to create covalent linkages.
• subject encompasses mammals and non-mammals.
• mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and 'guinea pigs, and the like.
• non-mammals include, but are not limited to, birds, fish and the like.
• the mammal is a human.
• a "disorder associated with HIV infection” or “disease associated with HIV infection” refers to a disease state which is marked by HIV infection.
• disorders associated with HIV infection include, but are not limited to, AIDS, Kaposi's sarcoma, opportunistic infections such as those caused by Pneumocystis carinii and Mycobacterium tuberculosis; oral lesions, including thrush, hairy leukoplakia, and aphthous ulcers; generalized lymphadenopathy, shingles, thrombocytopenia, aseptic meningitis, and neurologic disease such as toxoplasmosis, cryptococcosis, CMV infection, primary CNS lymphoma, and HIV-associated dementia, peripheral neuropathies, seizures, and myopathy.
• a compound that "inhibits replication of human immunodeficiency virus (HlV)” means a compound that, when contacted with HIV, for example, via HIV-infected cells, effects a reduction in the amount of HIV as compared with untreated control. Inhibition of replication of HIV can be measured by various means known in the art, for example, the p24 assay.
• Wild HIV refers to a strain of HIV having one or more mutated or altered amino acids as compared with wild type.
• Multi-Drug Resistant HIV refers to one or more HlV strains that are resistant to treatment with one or more chemotherapeutic agents.
• treat include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis.
• the terms further include achieving a therapeutic benefit and/or a prophylactic benefit.
• therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
• compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
• an “effective amount”, “therapeutically effective amount” or “pharmaceutically effective amount” as used herein, refer to a sufficient amount of at least one agent or compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
• an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease.
• An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
• administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein, e.g., as discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions described herein are administered orally.
• composition means having no persistent detrimental effect on the general health of the subject being treated.
• pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic. i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
• composition refers to a biologically active compound, optionally mixed with at least one pharmaceutically acceptable chemical component, such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
• pharmaceutically acceptable chemical component such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
• carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.
• pharmaceutically acceptable derivative or prodrug refers to any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of formula I, which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or a pharmaceutically active metabolite or residue thereof.
• Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing orally administered compound to be more readily absorbed into blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system).
• salts refers to salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
• Compounds described herein may possess acidic or basic groups and therefore may react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
• These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
• Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral or organic acid or an inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, di ⁇ itrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate
• metaphosphate methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1 -napthalenesulfonate, 2-napthalenesulfonatc, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconatc and xylcnesulfonate.
• acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
• a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
• alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
• bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (CM alkyl) 4 , and the like.
• Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they may contain. Water or oil-soluble or dispersible products may be obtained by such quatemization. See, for example, Berge et al., supra.
• prodrugs of the compounds described herein include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters.
• Various forms of prodrugs are well known in the art. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H.
• prodrugs described herein include, but are not limited to,, the following groups and combinations of these groups; amine derived prodrugs:
• Hydroxy prodrugs include, but are not limited to acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters and disulfide containing esters.
• the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
• the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
• An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
• pharmaceutical combination refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
• fixed combination means that at least one of the> compounds described herein, and at least one co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
• non-fixed combination means that at least one of the compounds described herein, and at least one co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the patient.
• cocktail therapies e.g. the administration of three or more active ingredients.
• co-administration are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
• the compounds described herein will be co-administered with other agents.
• These terms encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present.
• the compounds of the invention and the other agent(s) are administered in a single composition.
• compounds of the invention and the other agent(s) are admixed in the composition.
• metabolite refers to a derivative of a compound which is formed when the compound is metabolized.
• active metabolite refers to a biologically active derivative of a'compound that is formed when the compound is metabolized.
• the term "metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism.
• enzymes may produce specific structural alterations to a compound.
• cytochrome P450 catalyzes a variety of oxidative and reductive reactions
• uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic " alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).
• dashed line represents a double bond that may be located either between A and C(V) or between C(V) and D;
• A is S or C(Z);
• D is S or C(W); provided that one and only one of A and D is S;
• T is NH, O, or S
• W and Z are, independently, H, F, Cl, Br, C 1 -C 6 alkyl; C 2 -C 6 alkenyl; OC 1 -C 6 alkyl; C 3 -C 6 cycloalkyl; OC 3 -C 6 cycloalkyl, phenyl, or benzyl, wherein alkyl, alkenyl, cycloalkyl, and phenyl groups and the phenyl moiety of the benzyl group are optionally substituted with 1-3 groups selected from halogen, CF 3 , C 1 -C 3 alkyl, and OC 1 -C 3 alkyl
• V is H, halogen, C r C 6 alkyl; or V and W, together with the ring atoms to which they are attached, form an additional, fused 5-, 6-, or 7- membered ring, optionally containing one or two heteroatoms, which additional ring may be saturated, unsaturated, or aromatic; or V and Z, together with the ring atoms to which they are attached, form an additional, fused 5-, 6-, or 7- membered ring, optionally containing one or two heteroatoms, which additional ring may be saturated, unsaturated, or aromatic;
• Ar is selected from (a), (b), (c), and (d) below:
• R 4 , R 5 and each R 6 are independently selected from H, F, Cl, Br, CH 3 , CF 3, CH 2 F, CHF 2 , isopropyl, cyclopropyl, OCH 3 , OH, OCF 3 , NH 2 , and NHCH 3 , or
• Q and Q 1 are independently selected from N and CH;
• R 7 is Cl, Br, I, CH 3 , CF 3 , OCH 3 , isopropyl, cyclopropyl, /-butyl, or cyclobutyl;
• R 8 - R" are, independently, H or CH 3 .; or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, ester., tautomer or prodrug thereof.
• this invention provides a compound of formula IA, in which the 6-linker T in formula I is T', which may be O or S.
• the invention provides or contemplates a compound of formula IA where Ar is selected from 2-chloro-4-cyclopropyl phenyl; 2-methyl-4-cyclopropyl-naphth-l-yl; 2,6-dimethyl-4- cyanophenyl; 2,6-dimethoxy-4-cyanophenyl; 2,6-dimethyl-4-(2-cyanoethenyl) phenyl; 2,6-dimethoxy-4-(2- cyanoethenyl) phenyl; 2-methyl-4-cyclo ⁇ ropyl phenyl; 2,6-dimethyl-4-cyclopropyl phenyl; 2,6-di- trifluoromethyl-4-cyclopropyl phenyl; 2,4,6-trimethyl phenyl; and 2,6-dimethyl-4-acetyl phenyl.
• Ar is selected from 2-chloro-4-cyclopropyl phenyl; 2-methyl-4-cyclopropyl-nap
• the invention contemplates a compound of formula IA where Ar is selected from the following: 5-cyclopropyl-8-quinolyl; 5-isopropyl-8-quinolyl; 5-cyano-8-quinolyl; 5- cyclopropyl-7-trifluoromethyl-8-quinolyl; 5-acetyl-8-quinolyl; 5-cyano-7-methoxy-8-quinolyl; 5-cyano-7- methyl-8-quinolyl; S-cyclopropyl ⁇ -trifluoromethoxy-S-isoquinolyl; 5-cyano-8-isoquinolyl; 5-cyano-7-methoxy- 8-isoquinolyl; 5-cyano-7-methyl-8-isoquinolyl; S-cyclobutyl ⁇ -difluoromethyl- ⁇ -isoquinolyl; 5,7-dimethyl-8- cinnolyl; 5-cyclopropyl-7-methyl-8-cinnolyl; and 5-(2-cyanoethyl ⁇ -difluoromethyl-
• the invention provides a compound of formula IA-2
• this invention provides a compound of formula IA-4
• the invention provides a compound of formula IB where Ar is (c).
• this invention provides a compound of formula IB-I .
• this invention provides a compound of formula IB-2.
• the invention provides compounds of any of IA-I , IA-2, IA-3, IA-4, IB-
• the invention provides compounds of any of IA-I, IA-2, IA-3,
• the invention provides compounds of any of IA-I , IA-2, IA-3,
• the invention provides compounds of any of JA-I, IA-2, IA-3,
• this invention provides or contemplates a compound of formula IA-I , IA-2, IA-3, or IA-4, where Ar is 2,6-disubstituted-4-cyclopropyl, 2,6-disubstiruted-4-acctyl,
• this invention provides or contemplates compounds of formula IA-I , IA-2, IA-3, or IA-4, where Ar is 4-cyano-2,6-di-methoxy phenyl or 4-cyano-2,6-di-methyl phenyl.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where V is H, halo, or methyl.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where A is S and W is H, phenyl, or benzyl.
• this invention provides or contemplates a compound of formula IA-I, IA-2, IA-3, or IA-4, where A is S and W is H, C 3 -C 6 cycloalkyl, or OC 3 -C 6 cycloalkyl.
• this invention provides or contemplates compounds of formula IA-1, 1A-2, IA-3, or IA-4, where A is S and W is H, unsubsrituted C 1 -C 4 alkyl, monosubstiruted Ci-C 4 alkyl, or C 2 -C 3 alkenyl.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where A is S and W is H, halo, halomethyl, or methyl.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where A is S and V and W, together with the ring atoms to which they are attached, form an additional, fused 5-, 6-, or 7- membered carbocyclic ring.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where A is S and V and W, together with the ring atoms to which they are attached, form an additional, fused 5-, 6-, or 7- membered ring, which ring contains one or two heteroatoms selected from O, N, and S.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where D is S and Z is H, Ci-C 6 alkyl, or C 2 -Ce alkenyl.
• this invention provides or contemplates compounds of formula IA-I , IA-2, IA-3, or IA-4, where D is S and Z is H, Cj-C 6 cycloalkyl, or OC 3 -C 6 cycloalkyl.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where D is S and Z is H, unsubstituted C r C 4 alkyl, monosubstituted C 1 -C 4 alkyl, or C 2 -C 3 alkenyl.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where D is S and Z is H, halo, halomethyl, or methyl.
• this invention provides or contemplates a compound of formula IA-I, IA-2, IA-3, or IA-4, where D is S and Z is H, phenyl, or benzyl.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where D is S and V and Z, together with the ring atoms to which they are attached, form an additional, fused 5-, 6-, or 7- membered carbocyclic ring.
• this invention provides or contemplates compounds of formula IA-I, IA-2, IA-3, or IA-4, where D is S and V and Z, together with the ring atoms to which they are attached, form an additional, fused 5-, 6-, or 7- membered ring, which ring contains one or two heteroatoms selected from O, N, and S.
• Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
• Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
• Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc.
• Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.
• AHyI blocking groups are useful in then presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts.
• an allyl-blocked carboxylic acid can be deprotected with a Pd-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
• Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
• Protecting or blocking groups may be selected from:
• R2H is aniline, phenol or thiophenol, optionally substituted
• the compounds described herein may exist as geometric isomers.
• the compounds described herein may possess one or more double bonds.
• the compounds presented herein include all cis, trans, syn, anti,
• E
• Z
• compounds may exist as tautomers.
• the compounds described herein include all possible tautomers within the formulas described herein.
• the compounds described herein may possess one or more chiral centers and each center may exist in the R or S configuration.
• the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
• mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion may also be useful for the applications described herein.
• the compounds described herein can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds described herein, dissociable complexes are preferred (e.g., crystalline diastereomeric salts).
• Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
• the diastereomers can be separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
• the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
• a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley And Sons, Inc., 1981, herein incorporated by reference in its entirety. Labeled compounds of formula I
• isotopically-labeled compounds of formula I and methods of treating disorders.
• the invention provides for methods of treating diseases, by administering isotopically- labeled compounds of formula I.
• the isotopically-labeled compounds of formula 1 can be administered as pharmaceutical compositions.
• compounds of formula I also include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2 H, 3 H, 13 C, ' 4 C. ' 5 N, 18 O, ' 7 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
• Compounds described herein, pharmaceutically acceptable salts, esters, prodrugs, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
• isotopically-labeled compounds of formula I for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
• Tritiated, i. e., 3 H and carbon-14, i. e., 14 C 5 isotopes are particularly preferred for their ease of preparation and detcctability. Further, substitution with heavier isotopes such as deuterium, i.
• lsotopically labeled compounds can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, lsotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof can generally be prepared by carrying out procedures described herein, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
• compositions are also described herein.
• pharmaceutically acceptable salts of compounds of formula I and methods of treating disorders are also described herein.
• the invention provides for methods of treating diseases, by administering pharmaceutically acceptable salts of compounds of formula 1.
• the pharmaceutically acceptable salts of compounds of formula I can be administered as pharmaceutical compositions.
• the compounds described herein can be prepared as pharmaceutically acceptable salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
• Base addition salts can also be prepared by reacting the free acid form of the compounds described herein with a pharmaceutically acceptable inorganic or organic base, including, but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, rromethamine, N-methylglucamine, and the like and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
• the salt forms of the disclosed compounds can be prepared using salts of the starting materials or intermediates.
• the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric.acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, rnaleic acid, fumaric acid, Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulf
• solvates of compounds of formula I and methods of treating disorders.
• the invention provides for methods of treating diseases, by administering solvates of compounds of formula I.
• the solvates of compounds of formula I can be administered as pharmaceutical compositions.
• Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, cthanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.
• hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
• organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
• the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
• polymorphs of compounds of formula I and methods of treating disorders.
• the invention provides for methods of treating diseases, by administering polymorphs of compounds of formula 1.
• the polymorphs of compounds of formula I can be administered as pharmaceutical compositions.
• the compounds described herein include all their crystalline forms, known as polymorphs.
• Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs may have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
• prodrugs of compounds of formula I and methods of treating disorders.
• the invention provides for methods of treating diseases, by administering prodrugs of compounds of formula I.
• the prodrugs of compounds of formula I can be administered as pharmaceutical compositions.
• Prodrugs are generally drug precursors that, following administration to a subject and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway.
• Some prodrugs have a chemical group present on the prodrug that renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved and/or modified from the prodrug the active drug is generated.
• Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not.
• the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
• An example, without limitation, of a prodrug would be a compound as described herein which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
• a further example of a prodrug might be a short peptide (polyamino acid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
• Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues.
• the design of prodrugs to date has been to increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent. See, e.g.. Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 ( 1994); Hochhaus et al., Biomett. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.
• prodrug derivatives of compounds described herein can be prepared by methods ' known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
• appropriate prodrugs can be prepared by reacting a non-derivatized compound of formula 1 with a suitable carbamylaring agent, such as, but not limited to, 1,1- acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
• Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein are included within the scope of the claims. Indeed, some of the herein-described compounds may be a prodrug for another derivative or active compound.
• prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e. g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present invention.
• the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed.
• Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
• free carboxyl groups can be derivatized as amides or alkyl esters.
• Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews 1996, 19, 115.
• Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
• the present invention also provides methods for treating or ameliorating HIV disease and related diseases.
• the method includes administering a therapeutically effective dosage of at least one compound of the invention to a subject suffering from HIV disease or HIV-related diseases.
• the invention also provides a method of combination therapy in which one or more compound of the invention is administered in combination with one or more other compound having activity against HIV disease or HIV-related disease.
• the invention provides methods for inhibiting drug resistant HIV mutants.
• the high replication rate of HIV leads to genetic variants (mutants), especially when selective pressure is introduced in the form of drug treatment.
• the mutants frequently display resistance to anti-viral agents previously administered to the patient.
• Switching agents or using combination therapies may decrease or delay resistance, but because viral replication is not completely suppressed in single drug treatment or even with a two-drug combination, drug- resistant viral strains ultimately emerge.
• Triple drug combinations employing one (or two) nucleoside analogs and two (or one) non-nucleoside inhibitor (NNI) targeting RT provide a very promising therapy to overcome the drug resistance problem.
• RT mutant strains resistant to such a triple action drug combination would most likely not be able to function.
• Many mutant strains have been characterized as resistant to NNI compounds, including LlOOl, K103N, V106A. E138K, Y181C and Y188H. In particular, the Y181C and K103N mutants may be the most difficult to treat, because they are resistant to most of the NNI compounds that have been examined.
• the pharmaceutical compositions comprise an effective amount of a compound formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In some embodiments, the pharmaceutical compositions comprise an effective amount of a compound formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof and at least one pharmaceutically acceptable carrier. In some embodiments the pharmaceutical compositions are for the treatment of disorders. In some embodiments the pharmaceutical compositions are for the treatment of disorders in a mammal. In some embodiments the pharmaceutical compositions are for the treatment of disorders in a human. In some embodiments the pharmaceutical compositions are for the treatment of HIV/ AIDS.
• Described herein are compounds of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. Also described, are pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
• the compounds and compositions described herein may be administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. [00192
• intraduodenal routes include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical, and rectal administration.
• compounds described herein can be administered locally to the area in need of treatment. This may be achieved by, for example, but not limited to, local infusion during surgery, topical application, e.g., cream, ointment, injection, catheter, or implant, said implant made, e.g., out of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
• the administration can also be by direct injection at the site (or former site) of a tumor or neoplastic or preneoplastic tissue.
• the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
• Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient may also be presented as a bolus, electuary or paste.
• Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• Tablets may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
• the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
• suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
• stabilizers may be added.
• Dragee cores are provided with suitable coatings.
• concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
• compositions may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
• Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
• the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
• sterile liquid carrier for example, saline or sterile pyrogen-free water
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
• Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
• the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
• compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
• the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
• Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
• compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
• compositions may be administered topically, that is by non-systemic administration.
• systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
• compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
• the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the formulation.
• compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
• Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
• the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
• compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
• the compounds or compositions described herein can be delivered in a vesicle, e.g., a liposome (see, for example, Langer, Science 1990, 249,1527-1533; Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Bernstein and Fidler, Ed., Liss, N.Y., pp. 353-365, 1989).
• a vesicle e.g., a liposome
• the compounds and pharmaceutical compositions described herein can also be delivered in a controlled release system.
• a pump may be used (see, Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201 ; Buchwald et al. Surgery, 1980 88, 507; Saudek et al. N.
• compositions described herein can also contain the active ingredient in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
• compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
• Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipicnts may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as macrocrystalline cellulose, sodium crosscarmellose, com starch, or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
• the tablets may be un- coated or coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, or cellulose acetate butyrate may be employed as appropriate.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
• Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan
• the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
• preservatives for example ethyl, or n- propyl p-hydroxybenzoate
• coloring agents for example ethyl, or n- propyl p-hydroxybenzoate
• flavoring agents such as sucrose, saccharin or aspartame.
• sweetening agents such as sucrose, saccharin or aspartame.
• Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
• Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
• These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha- tocopherol.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. [00209] Pharmaceutical compositions may also be in the form of an oil-in-water emulsions.
• the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
• Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
• sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
• Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
• compositions may be in the form of a sterile injectable aqueous solution.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• the sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
• the active ingredient may be first dissolved in a mixture of soybean oil and lecithin.
• the oil solution then introduced into a water and glycerol mixture and processed to form a microemulsion.
• the injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection.
• a continuous intravenous delivery device may be utilized.
• An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
• the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• compositions may also be administered in the form of suppositories for rectal administration of the drug.
• These compositions can be prepared by mixing the inhibitors with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non- irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
• topical application can include mouth washes and gargles.
• compositions may be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
• suitable intranasal vehicles and delivery devices or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
• the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
• the amount of pharmaceutical compositions administered will firstly be dependent on the mammal being treated.
• the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, sex, diet, weight, general health and response of the individual patient, the severity of the patient's symptoms, the precise indication or condition being treated, the severity of the indication or condition being treated, time of administration, route of administration, the disposition of the composition, rate of excretion, drug combination, and the discretion of the prescribing physician.
• the route of administration may vary depending on the condition and its severity.
• the pharmaceutical composition is in unit dosage form.
• the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. The amount and frequency of administration of the compounds described herein, and if applicable other therapeutic agents and/or therapies, will be regulated according to the judgment of the attending clinician (physician) considering such factors as described above. Thus the amount of pharmaceutical composition to be administered may vary widely.
• Administration may occur in an amount of between about 0.001 mg/kg of body weight to about 100 mg/kg of body weight per day (administered in single or divided doses), more preferably at least about 0.1 mg/kg of body weight per day.
• a particular therapeutic dosage can include, e.g., from about 0.01 mg to about 7000 mg of compound, and preferably includes, e.g., from about 0.05 mg to about 2500 mg.
• the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, preferably from about 1 mg to 300 mg, more preferably 10 mg to 200 mg, according to the particular application.
• dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day.
• the amount administered will vary depending on the particular IC 5O value of the compound used. In combinational applications in which the compound is not the sole therapy, it may be possible to administer lesser amounts of compound and still have therapeutic or prophylactic effect.
• the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
• the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
• the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
• Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
• Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
• the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
• excipients such as citric acid
• disintegrants such as starch, alginic acid and certain complex silicates
• binding agents such as sucrose, gelatin and acacia.
• lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
• Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
• Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols.
• active compound may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
• the compounds described herein or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof may be administered as a sole therapy.
• the compounds described herein or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof may also be administered in combination with another therapy or therapies.
• one of the side effects experienced by a patient upon receiving one of the compounds described herein is hypertension, then it may be appropriate to administer an anti-hypertensive agent in combination with the compound.
• the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
• the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
• a treatment for HIV/AIDS involving administration of one of the compounds described herein increased therapeutic benefit may result by also providing the patient with another therapeutic agent for HIV/AIDS.
• the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
• Other therapies include, but are not limited to administration of other therapeutic agents.
• the compounds described herein need not be administered in the same pharmaceutical composition as other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route.
• the compounds/compositions may be administered orally to generate and maintain sufficient blood levels thereof, while the other therapeutic agent may be administered intravenously.
• the determination of the. mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician.
• the initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
• the particular choice of compound will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.
• the present invention provides methods for treating or ameliorating HIV disease and related diseases.
• the method includes administering a therapeutically effective dosage of at least one compound of the invention to a subject suffering from HIV disease or HIV-related diseases.
• the invention also provides a method of combination therapy in which one or more compound of the invention is, administered in combination with one or more other compound having activity against HIV disease or HIV-related disease. Kits
• kits for the treatment of disorders such as the ones described herein.
• kits comprise a compound, compounds or compositions described herein in a container and, optionally, instructions teaching the use of the kit according to the various methods and approaches described herein.
• kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider..
• Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials.
• Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.
• the compounds described herein can be utilized for diagnostics and as research reagents.
• the compounds described herein, either alone or in combination with other compounds, can be used as tools in differential and/or combinatorial analyses to elucidate expression patterns of genes expressed within cells and tissues.
• expression patterns within cells or tissues treated with one or more compounds are compared to control cells or tissues not treated with compounds and the patterns produced are analyzed for differential levels of gene expression as they pertain, for example, to disease association, signaling pathway, cellular localization, expression level, size, structure or function of the genes examined.
• These analyses can be performed on stimulated or unstimulated cells and in the presence or absence of other compounds which affect expression patterns.
• the compounds and formulations of the present invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
• R 2 H (defined as a substituted or unsubstituted aniline, a substituted or unsubstituted phenol or a substituted or unsubstituted thiophenol) was coupled on the ring system with trifluoroethanol and trifluoroacetic acid (when R 2 H is a substituted or unsubstituted aniline), sodium hydride (when R 2 H is a substituted or unsubstituted phenol), or DBU (when R 2 H is a substituted or unsubstituted thiophenol).
• 4-Amino benzonitrile was coupled in the presence of trifluoroethanol and trifluoroacetic acid to provide a series of thieno[2,3-rf]pyrimidine compounds with various R 2 substitutions.
• R 2 H (defined as a substituted or unsubstituted aniline, a substituted or unsubstituted phenol or a substituted or unsubstituted thiophenol) was coupled on the ring system with trifluoroethanol and trifluoroacetic acid (when R 2 H is a substituted or unsubstituted aniline), sodium hydride (when R 2 H is a substituted or unsubstituted phenol), or DBU (when R 2 H is a substituted or unsubstituted thiophenol).
• R 2 H (defined as above) was coupled on the ring system with trifluoroethanol and trifluoroacetic acid (when R 2 H is a substituted or unsubstituted aniline), sodium hydride (when R 2 H is a substituted or unsubstituted phenol), or DBU (when R 2 H is a substituted or unsubstituted thiophenol).
• 4-Aminobenzonitrile was coupled in the presence of trifluoroethanol and trifluoroacetic acid to provide a series of 7-rnethylthieno[3,2-d]pyrimidine compounds with various R 2 substitutions.
• Example 16 7-Methylthieno[3,2-d]pyrimidine-2,4(lH,3H)-dione
• HIV-I human immunodeficiency virus type 1
• VSV-G vesicular stomatitis virus envelope glycoprotein
• Human immunodeficiency virus type 1 uses lipid raft-co-localized CD4 and chemokine receptors for productive entry into CD4+ T cells. It should be particularly appreciated that the virus contains two introduced mutations in the RT gene (K103N and Y181C, created by PCR mutagenesis) that render the virus highly resistant to current non-nucleoside HlV-I drugs.
• Virus stocks were generated by cotransfection of plasmid DNA encoding VSV-G with vector ⁇ NL4-3Env(-)Luc(+) into 293T cells. Sixty-four hours after transfection, virus-containing medium was collected by centrifugation and stored frozen at -80° C.
• HeLa cells were infected with the VSV-G pseudotyped virus in the presence of screening compounds in a 384-well micro l iter plate format. Forty-eight hours after initial infection, lysis buffer and Luciferase Assay Reagent (Promega) was added to the cells and luciferase activity was determined by counting the resultant luminescence using a LJL luminometer. Since the luciferase gene is carried in the virus genome, its expression level directly reflects the virus replication level in the presence of a compound.
• the HeLa- JC53 cell line that expresses high levels of CD4 and CCR5 (see e.g., Platt et al. in Journal of Virology (1998), 72: 2855-2864: Effect of CCR5 and CD4 cell surface concentrations on infection by macrophagetropic isolates of human immunodeficiency virus type 1) was modified by isolation of a stable cell line that expresses luciferase under the control of the HIV-I promoter (long terminal repeat, i.e., LTR).
• HIV-I infection of this cell line stimulates the transcription of luciferase from the HTV-I promoter and the luciferase gene expression level is proportional to the level of virus replication (Harrington et al. in Journal of Virology Methods (2000), 88: 11 1- 115: Direct detection of infection of HIV-I in blood using a centrifugation-indicator cell assay; and Roos et al. in Virology (2000), 273: 307-315: LuSIV cells: a reporter cell line for the detection and quantitation of a single cycle of HlV and SIV replication). Procedures for virus infection, compound testing and luciferase activity determination were the same as for the VSV-G pseudotyped HIV-I .
• the first approach employed another modified HeLa-JC53 cell line that constitutively expresses high level of luciferase without virus infection. The level of luciferase expression in these cells served as an indicator for cell replication in the presence of the compounds. Procedures for compound testing and luciferase activity determination were the same as for the virus infection tests.
• the other toxicity assay utilized HeLe-JC53 cells and a commercially available MTS assay kit (Promega) that measures the mitochondria function of the cells. Results

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